Cell division in eukaryotic cells is divided into two sequential phases, mitosis followed by cytokinesis. At the onset of mitosis, cytoplasmic microtubules disassemble into tubulin molecules which are then polymerized to form the mitotic spindle. The mitotic spindle, an element of the mitotic apparatus, ensures that replicated chromosomes are precisely divided between the two daughter cells at division. The polymerization of tubulin to form the mitotic spindle is highly sensitive to chemical agents which bind tubulin. Colchicine, for example, has long been known to inhibit the polymerization of tubulin. When administered to a dividing cell, colchicine causes the mitotic spindle to disappear and blocks mitosis. Anticancer drugs such as vinblastine and vincristine induce the formation of paracrystalline aggregates of tubulin and thus deplete the supply of tubulin available for the formation of the mitotic spindle. Absence of the spindle, of course, interrupts mitosis and prevents cell division. Cells thus blocked from division ultimately die. Rapidly dividing cells such as cancer cells are preferentially killed by this prevention of cell division.
Applicants have now discovered a new class of antimitotic agents which prevent spindle formation by causing tubulin aggregation as do vinblastine and vincristine. These new antimitotic agents are, however, much less toxic than are other antimitotic agents and thus should be preferred for therapeutic use in controlling the growth of tumor tissue and in the treatment of gout.
Myelin is a fatty coating surrounding the axons of the nervous system and serves to insulate the electrical signals in the axons. By insulating the axons, nerve impulses are transmitted more rapidly and efficiently. In the peripheral nervous system, myelin is produced by and is a part of the cell surface of Schwann cells, a set of cells which lie parallel to the axons. The myelin of each Schwann cell is used to surround a single axon. In the central nervous system, the insulating myelin sheaths are produced by the oligodendroglial cells. Unlike the Schwann cells, the myelin of an oligodendroglial cell may surround many axons.
Multiple sclerosis is a demyelinating disease in which the myelin sheaths of the central nervous system are destroyed. Once destroyed, the axons are left exposed and are unable to effectively transmit nerve impulses. Symptoms include loss of visual acuity, muscular weakness, and spasticity. Typically the victim of multiple sclerosis will experience periods where the symptoms are exacerbated followed by periods where the symptoms nearly vanish. The course of the disease is normally progressive and recovery between periods of exacerbation is diminished, the length of time between periods of exacerbations is reduced, and the length of each period of exacerbation increases. The cause of multiple sclerosis is unknown but the most recent evidence increasingly supports the notion of a viral agent or autoimmunological source. Indeed the lesions of multiple sclerosis are mimicked by the lesions of experimental allergic encephalomyelitis, an experimentally induced autoimmunological disorder in which the myelin sheaths of the central nervous are destroyed. This immunological connection has prompted the use of various immunosuppressive agents such as azathioprine, cyclophosphamide, and cyclosporin A to treat multiple sclerosis. Applicants have now discovered that certain chalcone derivatives inhibit the destruction of the myelin sheath in the central nervous system as evidenced by the inhibition of paralysis of hind limbs in test animals and are thus useful in the treatment of multiple sclerosis.